Summary Despite major advances in pacemaker technologies during the past decade, current pacemaker systems still suffer from several critical limitations. Primarily, the need to implant pacemaker leads within cardiac chambers could lead to a host of complications such as infection, thrombosis, tricuspid valve and ventricular perforation, along with the complications associated with the extraction of the lead when required. Furthermore, with traditional pacemakers, the cardiac regions accessible to pacing are restricted to right ventricle (RV, typically at the apex) and occasionally, coronary sinus distribution in cases of biventricular pacing. RV pacing creates abnormal left ventricular (LV) contraction, reduced pump function, hypertrophy, ultrastructural abnormalities and increases risk of atrial fibrillation, ventricular arrhythmias and ultimately heart failure and death. Leadless pacemakers address the issue associated with intravascular leads, but they remain limited in pacing only the RV and require placement of a new pacemaker after battery depletion. The recently developed remote ultrasound- powered wireless LV pacing electrode in conjunction with traditional pacemaker for biventricular pacing is technically limited by need for an acoustic window free of rib cage and lung on the transmission path to the electrode and the high density ultrasound drains battery quickly. To overcome the limitations of currently available pacemakers, we propose to develop the next generation of pacemaker system composed of wireless, miniaturized, battery-free, radiofrequency (RF) microwave activated sensor/stimulator electrodes that could be implantable and controlled by a remote pulse generator. In Aim 1, we will pursue technical development of miniaturized wireless sensor/stimulator electrodes, operating as a stand-alone platform, and remote pulse generator controller to monitor simulated cardiac signals and provide pacing signals using Micro-Electro-Mechanical-Systems (MEMS) and RF technologies on an organic phantom model while testing safety by measuring heat generation and extraneous RF interference. In Aim 2, we will test the wireless pacemaker system in vitro by measuring signal detection, pacing stimulation and tissue safety on our validated biomimetic cardiac micro-tissue model, using human induced pluripotent stem cell derived CMs (hiPSCs-CMs), as well as in vivo using a rodent thoracotomy model. We envision that the proposed innovative wireless pacemaker system could usher a paradigm shift in pacemaker therapeutics through the ability to pace precise regions of the heart resulting in more physiologic pacing and optimization of cardiac performance. !